Improving outcomes in colorectal cancer: Where do we go from here?

Abstract

Colorectal cancer (CRC) places a considerable burden on individuals and society in Europe, being the second most common cause of cancer-related death in the region. While earlier diagnosis and advances in treatment have considerably improved survival in recent years, further progress is needed. One of the greatest challenges associated with the treatment of CRC is the fact that current therapies for advanced disease are not curative, necessitating treatment for many years and placing a significant healthcare burden on society. To reduce the burden of CRC, care delivery must be more efficient and cost-effective. In particular, development of adequate screening programmes is needed, along with chemo-preventative strategies and newer, more active therapies. Further challenges include the lack of optimal selection of patients for adjuvant therapy, identification of the most appropriate target populations for current treatments and the optimum sequence for new molecular targeted agents. This article outlines current developments and unmet needs in CRC, and provides a detailed vision for improvements in the management of the disease. Implementation of some of these strategies will go some way to improving outcomes for patients with CRC.

An Unconventional KITENIN/ErbB4-Mediated Downstream Signal of EGF Upregulates c-Jun and the Invasiveness of Colorectal Cancer Cells

“…5D). Although the detailed mechanisms of what exactly EGF binds to, how ErbB4 assists in processing KITENIN-bound phospho-Dvl2, and how lowered phospho-Dvl2 within the KITENIN/ ErbB4 complex stabilizes c-Jun are unknown, the downstream signal of EGF, the KITENIN/ErbB4-Dvl2-c-Jun pathway, that we identified in this study differs from the previously reported downstream pathways of EGF that require binding to EGFR (3)(4)(5)(6). Thus, we have identified a new EGFR-independent promotility signal of EGF in colorectal cancer cells.…”

“…S8A). To examine whether the expression levels of KITENIN affected the survival of colorectal cancer cells in response to cetuximab, we first chose Caco2 colorectal cancer cells, a KRAS/BRAF wild-type cell line (23), as these would be suitable models for the clinical setting where EGFR-targeted therapy is used (5,6). Although there was no difference in survival to cetuximab between empty vector-and KITENIN-transfected Caco2 cells, highly KITENIN-expressing Caco2 cells were resistant to cetuximab, whereas KITENIN-knockdown Caco2 cells showed increased sensitivity (Supplementary Fig.…”

“…One reason for this lack of response is the heterogeneity of colorectal cancers. In previous studies, colorectal cancers lacking oncogenic alterations in KRAS, BRAF, PIK3CA, and PTEN genes (so-called "quadruple negative" tumors) were shown to have the highest probability of a response to anti-EGFR therapy (5,6). However, approximately 20% of patients with metastatic colorectal cancer who show no response to anti-EGFR targeted therapies do not harbor mutations in KRAS, BRAF, and PIK3CA, nor loss of PTEN expression (7).…”

Induction of cell proliferation, clonogenicity and cell accumulation in S phase as a consequence of human UBE2Q1 overexpression

“…The efficiency of transfection was assessed by fluorescence microscopy (Helmut Hund GmbH, Wetzlar, Germany) of GFP-tagged UBE2Q1 protein, and confirmed by western blot analysis. The selection medium was replaced every 3 days, and individual clones (7)(8) were isolated and propagated 21-28 days post-transfection. These clones were isolated as stable transfectants.…”

“…In spite of improvements in diagnosis and adjuvant therapy of CRC (7)(8)(9), the mortality rate for CRC is still ~40% (10). Therefore, a critical study for uncovering the biological mechanisms underlying the progression of CRC could lead to more efficient treatment strategies (11).…”